Abstract
Dengue virus has emerged as an important arboviral infection worldwide. As a complex pathogen, with four distinct serotypes, the development of a successful Dengue virus vaccine has proven to be challenging. Here, we describe a novel Dengue vaccine candidate that contains truncated, recombinant, Dengue virus envelope protein from all four Dengue virus serotypes (DEN-80E) formulated with ionizable cationic lipid nanoparticles (LNPs). Immunization studies in mice, Guinea pigs, and in Rhesus macaques, revealed that LNPs induced high titers of Dengue virus neutralizing antibodies, with or without co-administration or encapsulation of a Toll-Like Receptor 9 agonist. Importantly, LNPs were also able to boost DEN-80E specific CD4+ and CD8+ T cell responses. Cytokine and chemokine profiling revealed that LNPs induced strong chemokine responses without significant induction of inflammatory cytokines. In addition to being highly efficacious, the vaccine formulation proved to be well-tolerated, demonstrating no elevation in any of the safety parameters evaluated. Notably, reduction in cationic lipid content of the nanoparticle dramatically reduced the LNP’s ability to boost DEN-80E specific immune responses, highlighting the crucial role for the charge of the LNP. Overall, our novel studies, across multiple species, reveal a promising tetravalent Dengue virus sub-unit vaccine candidate.
Highlights
T cell responses in comparison to live-attenuated vaccines and often do not yield CD8+T-cell responses[9,10]
We evaluated the ability of Merck lipid nanoparticles (LNPs) to boost immune responses to a recombinant, truncated envelope protein from Dengue virus (DENV) serotype 2 (DEN2-80E) In previously reported preclinical studies evaluating DEN-80E antigens, formulations containing ISCOMATRIXTM adjuvant were found to result in the strongest DENV neutralizing antibody titers in both mice and non-human primates, and it was selected as the comparator in the current studies[13,14] DENV’s envelope specific antibodies that possess neutralizing activity are currently the main focus of Dengue vaccine clinical trials[26]
LNP by itself at 25 μg and 125 μg, or TLR-ODN (2 μg and 10 μg) co-administered or encapsulated with LNP (25 μgand 125 μg), resulted in statistically significant DENV serotype 2 (DEN2) virus neutralization titers. These data strongly suggest that LNP adjuvant by itself was able to induce strong DEN2-80E specific antibody responses that were functionally effective at neutralizing Dengue Virus 2 infection
Summary
T cell responses in comparison to live-attenuated vaccines and often do not yield CD8+T-cell responses[9,10]. Development of a sub-unit Dengue vaccine has focused on the Dengue virus envelope (env) as the antigen, formulated with various vaccine adjuvants[11,12]. The live-attenuated Dengue vaccine strategies either utilize chimeric viral vectors that express Dengue virus envelope proteins[15,16] or uses live-attenuated Dengue virus backbone of one serotype to express proteins of all four Dengue serotypes[17,18] These vaccines generate both B-cell (nAb) and T-cell responses. We report extensive preclinical evaluation of immunogenicity and safety, which demonstrate that LNP containing Dengue sub-unit vaccine formulations are well-tolerated, and elicit strong DEN-80E specific B-cell and T-cell responses in rodents and non-human primates
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